November/December 2020 Issue

Diabetes Drugs Update
By Carrie Dennett, MPH, RDN, CD
Today’s Dietitian
Vol. 22, No. 9, P. 30

What’s New, and What’s in the Pipeline

While nutrition and lifestyle are key components of diabetes management, so is medication. Development of new pharmaceutical drugs is a costly endeavor, and the Holy Grail involves creating new medications that aren’t only safe but also more effective than their predecessors at lowering A1c without increasing the risk of hypoglycemia or causing intolerable side effects. Today’s Dietitian looks at some of the newcomers—some approved, some still in the pipeline—that offer that, and more.

Oral GLP-1 Receptor Agonists
Glucagonlike peptide-1 (GLP-1) receptor agonist–based therapies improve glucose control through several mechanisms. One of two incretin (INtestinal secretion INsulin) hormones, GLP-1 is a gastrointestinal peptide released in response to food, stimulating insulin synthesis and secretion.1 Produced in the small intestine, GLP-1 binds to GLP-1 receptors found in various tissues, including pancreatic beta cells. GLP-1 receptor agonist drugs stimulate insulin release, inhibit inappropriate postmeal glucagon release, slow gastric emptying, and decrease appetite.2 They have another important benefit, says Andrew Bzowyckyj, PharmD, BCPS, CDE, an associate professor of pharmacy at Pacific University in Oregon. “There’s a much lower risk of hypoglycemia because they work in the incretin pathway and not in the insulin pathway,” he says. “Even just the fear of hypoglycemia can really hold people back.”

One drawback to GLP-1 receptor agonists—which include dulaglutide (Trulicity), exanatide (Byetta and Bydureon), liraglutide (Victoza), and lixisenatide (Adlyxin)—is that traditionally they’ve been delivered via injection pens, sometimes with visible needles. However, in 2019 the FDA approved an oral version of a new GLP-1 receptor agonist, semaglutide, under the brand name Rybelsus. Semaglutide was discovered in 2012 as a longer-lasting alternative to liraglutide, both of which are made by Novo Nordisk.3 Under the brand name Ozempic, semaglutide was first approved by the FDA in 2017 for use in managing type 2 diabetes in adults via a prefilled pen for once-weekly subcutaneous injection.4 Oral semaglutide demonstrated a similar efficacy as the injectable version in its phase III PIONEER (Peptide InnOvatioN for Early diabEtes tReatment) trials and is available in 3-, 7-, and 14-mg tablets.4,5

Could the availability of an oral GLP-1 agonist boost adherence for patients who need a GLP-1 agonist? Diana Isaacs, PharmD, BCPS, BC-ADM, CDE, a clinical pharmacy specialist at Cleveland Clinic Diabetes Center in Ohio, thinks it has the potential to do so. “Some people are very turned off by an injectable medication, and having an oral option will likely make GLP-1 agonists available to a wider range of people with type 2 diabetes,” she says. “This is important because guidelines now recommend use of a GLP-1 agonist or SGLT-2 inhibitor for people with type 2 diabetes and high cardiovascular risk, regardless of A1c.”

Bzowyckyj says oral semaglutide has the double benefit of helping patients avoid needles and hypoglycemia risk. “Needle anxiety is real, and I think the fear of insulin is extremely real, so when they find out that something is not insulin, they’re like, ‘Oh, OK,’” he says.

While needing to inject a medication can be a barrier to compliance for some patients, developing an oral form of a GLP-1 receptor agonist had been challenging for a few reasons. The stomach environment, with its low pH and presence of protein-degrading enzymes, damages protein- and peptide-based drugs, and the intestinal lining blocks many peptides and proteins from passing through to the bloodstream.6 Oral semaglutide is coformulated with sodium N-(8-[2-hydroxybenzoyl] amino) caprylate, which enhances absorption by raising the pH of the stomach.4

As with all GLP-1 receptor agonists, oral semaglutide is associated with gastrointestinal side effects such as nausea, abdominal pain, and vomiting. The benefits of an oral medication may be outweighed by a few downsides, at least for certain patients. Oral semaglutide should be taken at least 30 minutes before the first food, beverage, or other oral medications of the day, with no more than 4 oz of plain water only—challenging for patients prescribed other oral medications that should be taken first thing in the morning on an empty stomach.4

In January, the FDA approved injectable semaglutide for prevention of major adverse cardiovascular events, including death from CVD, nonfatal myocardial infarction, and nonfatal stroke in adults with type 2 diabetes and established CVD.7 In June 2019, Novo Nordisk began recruiting for a larger cardiovascular outcomes trial of oral semaglutide, enrolling 9,642 adults with type 2 diabetes and established CVD. The estimated completion date is July 2024.8

GLP-1/GIP Dual Agonist
GLP-1/GIP dual agonists go one step further, mimicking both GLP-1 and glucose-dependent insulinotropic polypeptide (GIP), also known as gastric inhibitory polypeptide. As with GLP-1, GIP is an incretin hormone, but unlike GLP-1, GIP weakly inhibits gastric enzymes to protect the small intestine from damage and slow gastric emptying, and it was originally thought that this was the hormone’s primary function. The intestines secrete both hormones in response to food intake to stimulate insulin secretion. In fact, GIP’s insulin-stimulating effects are even stronger than those of GLP-1.1,9

GIP receptor agonists traditionally haven’t been used in diabetes management for a few reasons. Unlike GLP-1, GIP increases glucagon release after meals—some studies have found that this happens even during hyperglycemia—and facilitates fat accumulation.1,2 Then there’s the problem of GIP resistance in people with type 2 diabetes—while GIP secretion appears to be normal, its insulin-stimulating ability is severely reduced at both physiological and pharmacological concentrations, possibly due to glucose-induced down-regulation of the GIP receptor.2 The bottom line is that people with type 2 diabetes are less responsive to the insulin-stimulating effects of GIP compared with those without diabetes, although this effect is most likely to be seen with increasing age and A1c levels.2,10

However, substantial research shows GIP resistance can be overcome mostly by other glucose-lowering therapies, such as GLP-1 receptor agonists.9 Also, using GIP in combination with GLP-1 can have several positive effects. For example, both GIP and GLP-1 can help preserve beta cell mass and function by inhibiting apoptosis (programmed cell death).1 In vitro studies of human pancreatic islets found that the combination of GLP-1 and GIP had synergistic effects on insulin synthesis, insulin secretion, and expression of genes associated with beta cell differentiation and survival, compared with using only one of the two,11 although animal studies have been inconsistent.2 In addition, dual GIP and GLP-1 receptor agonists achieve significantly better glucose control and weight loss compared with selective GLP-1 receptor agonists, such as exenatide or liraglutide, and fewer side effects than GLP-1 receptor agonists alone.9,12

Tirzepatide (LY3298176) is one promising dual agonist that has high affinity for both GLP-1 and GIP receptors. It’s administered as a once-weekly subcutaneous injection, with peak concentration between 24 and 48 hours. The most frequent side effects reported in clinical trials were gastrointestinal—vomiting, nausea, decreased appetite, diarrhea, and abdominal distension. All were dose dependent and considered mild to moderate in severity.9

Tirzepatide is still undergoing phase III clinical trials for type 2 diabetes, with several expected to be completed between October of this year and early 2022. A phase II trial compared four doses of tirzepatide—1 mg, 5 mg, 10 mg, and 15 mg—with a placebo and 1.5-mg doses of Lilly’s GLP-1 antagonist, dulaglutide. At 26 weeks, tirzepatide outperformed dulaglutide in A1c reductions. Fifty-two percent of patients in the dulaglutide group achieved the recommended A1c target of 7% or less, compared with 33% to 90% of patients in the tirzepatide groups—32.7% in the 1-mg group, 69.1% in the 5-mg group, 90% in the 10-mg group, and 77.4% in the 15-mg group. Percentages of patients reaching an A1c of 6.5% or less were 15.4%, 63.6%, 82%, and 58.5%, respectively, compared with 38.9% for dulaglutide. Moreover, 18% of the 10-mg dose group and 30.2% of the 15-mg dose group achieved an A1c of 5.7%, considered normal.13

Unfortunately, tirzepatide’s weak spot is likely to be tolerability. Bzowyckyj says the study dropout rate was 20% to 30%, depending on dose, because researchers messed up the titration—dosing increased too much, too fast, which increased side effects. “Offering a lower dose and delayed release formulations may help,” Bzowyckyj says. Still, he says he’s cautiously optimistic, given that overall A1c reduction was on the magnitude of 2%—the baseline was 8%. “I do want to see what this looks like in phase III studies.”

Tirzepatide is the only dual agonist currently being tested for type 2 diabetes management, as most companies developing multiagonists, including Novo Nordisk, are focusing on obesity or other health conditions. “There were some studies with others that were discontinued due to the high side effects,” Isaacs says. “I do think there are some others though in very early clinical trials. Tirzepatide is definitely looking the most promising right now for use in type 2 diabetes. And it also shows great weight loss. I am hopeful that with a slow titration the side effects will be manageable. I would love to have another drug option for use in people with type 2 diabetes.”

Dual SGLT inhibitor
One promising drug option that has yet to be FDA approved is sotagliflozin (Zynquista), the first dual sodium-glucose cotransporter (SGLT) inhibitor. SGLT-1 absorbs glucose in the intestines, while SGLT-2 resorbs glucose in the kidneys.14 Because SGLT-2 inhibitors—one of the newest classes of oral antihyperglycemic medications—reduce glucose reabsorption in the kidneys, allowing it to be excreted through the urine, they lower blood sugar without stimulating insulin release.15

The American Diabetes Association recommends SGLT inhibitors as long as people have kidney function better than 30 mL/min, due to some reports of acute kidney injury and medication ineffectiveness in advanced stages of kidney disease, but Bzowyckyj says overall this drug class has benefits for kidney health, helping to prevent and delay kidney injury. “When you send glucose into the kidneys, you’re punching the nephrons every time your body reabsorbs the sugar and then filters it out again. SGLT inhibitors prevent reabsorption, so the nephrons only get hit once, then the glucose gets excreted.”

“These drugs have actually demonstrated kidney protective effects, such as reducing albuminuria in people with type 2 diabetes,” Isaacs says. “And they also have amazing cardiovascular benefits—well, at least three out of the four do.” Results for ertugliflozin were neutral.16,17

In patients with type 2 diabetes not willing or not ready to start insulin but who need more glucose lowering than what metformin alone can achieve, SGLT-2 inhibitors are an option in those with acceptable risk factor profiles. They also promote weight loss and lower blood pressure.15 SGLT-2 inhibitors are available as single-ingredient products and as combination drugs with other diabetes medications such as metformin. The American Diabetes Association guidelines recommend that patients with type 2 diabetes who have established atherosclerotic CVD be prescribed a SGLT-2 inhibitor or a GLP-1 receptor agonist with demonstrated CVD benefit. Among patients with atherosclerotic CVD who also have, or are at high risk of, heart failure, SGLT-2 inhibitors are preferred.18

Most SGLT-2 inhibitors also can inhibit SGLT-1 but aren’t too effective at doing so. Sotagliflozin has been shown to be just as effective at inhibiting SGLT-2 as the SGLT inhibitors currently on the market but is more than 10 times more effective at inhibiting intestinal SGLT-1. This is important because it’s thought that SGLT-1 may become up-regulated when SGLT-2 is inhibited, making a dual SGLT-2/SGLT-1 inhibitor more effective overall.14

Currently, sotagliflozin is in phase III clinical trials for type 2 diabetes through the InSynchrony clinical program, in which it has demonstrated a statistically significant reduction in A1c in patients on metformin and those with stage 3 chronic kidney disease. Phase III trials (the inTandem trials) for sotagliflozin have been completed for type 1 diabetes, but it was narrowly denied FDA approval in January 2019 due to concerns about an observed risk of diabetic ketoacidosis in three phase III trials—an approximately eight-fold risk compared with placebo. The trials also found that sotagliflozin significantly improved glycemic control without increasing hypoglycemia.19-21

Sotagliflozin was approved last year in the European Union for use as an adjunct to insulin therapy to improve glycemic control in adults with type 1 diabetes and a BMI ≥27 kg/m2, who couldn’t achieve adequate glycemic control despite optimal insulin therapy. “I was very disappointed that sotagliflozin did not gain FDA approval,” Isaacs says. “However, it did in Europe, so I hope that we can gain some real-world data.”

The safety and efficacy of any SGLT-2 inhibitors haven’t been established in patients with type 1 diabetes, and the FDA hasn’t approved them for use in these patients. In fact, there are relatively few drugs in the type 1 diabetes pipeline. “Many people with type 1 diabetes use SGLT-2 inhibitors off label, but many can’t due to insurance restrictions since it’s not FDA approved,” Isaacs says. “While the type 1 market is smaller, pharma has invested money studying empagliflozin, dapagliflozin, and sotagliflozin in type 1 diabetes. It’s just unfortunate that the FDA did not approve any of them for use, due to the side effect risk.”

Glucagon Receptor Antagonist
While there’s hope for an eventual approval of sotagliflozin, approval of a glucagon receptor antagonist is more of a long shot. It might seem logical that a drug that would inhibit release of glucagon—and its breakdown into glucose—as well as prevent glucose production by the liver would be useful in diabetes management, but current attempts to develop such a drug have failed.

“It increases the amount of fat that goes into your liver, which is the opposite of what we want,” Bzowyckyj says. “If you look at the number of companies that have tried and then stopped, it’s not promising.”

Increased liver enzymes are the most significant side effect observed in studies, but also concerning is the potential for malignant transformation of pancreatic alpha cells. There’s also a slightly increased risk of hypoglycemia.22

“It’s an interesting concept for a drug target, but it’s too early to say if this will become a future drug option,” Isaacs says.

Final Thoughts
Looking at the big picture, what do the newer diabetes medications offer compared with what’s already on the market?

“SGLT-2 inhibitors are exciting as we learn more and more about their cardiovascular benefits,” Isaacs says. In fact, recently published results of a large multinational cohort study of 193,124 new users of an SGLT-2 inhibitor or a dipeptidyl peptidase-4 inhibitor found that SGLT-2 use was associated with a lower risk of cardiovascular events.23

Bzowyckyj says many potential new drugs still are in phase I clinical trials, and that the next boom might be seeking approval of adult type 2 diabetes drugs to be used in adolescent patients. In fact, this already has happened with the GLP-1 receptor agonist liraglutide, which was approved by the FDA in 2010 for use in adults for type 2 diabetes management, then approved in 2019 for pediatric patients aged 10 and older, making it the first noninsulin drug approved to treat type 2 diabetes in children since metformin was approved in 2000.24 Bzowyckyj adds that while not everyone with diabetes needs to lose weight, the newer drugs have benefits for, if not weight loss, then preventing weight gain. “We’re seeing in the studies some benefits for cardiovascular disease and kidney function … to me, it’s the icing on the cake.”

— Carrie Dennett, MPH, RDN, CD, is the nutrition columnist for The Seattle Times, owner of Nutrition By Carrie, and author of Healthy for Your Life: A Holistic Guide to Optimal Wellness.


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